Significance Simple and affordable intervention strategies are needed to reduce the rate of HIV transmission from mother to infant in developing countries. Objectives Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a useful animal model of human pediatric HIV infection to investigate whether short-term 9-[2-(phosphonomethoxy)-propyl]adenine (PMPA) administration can protect against perinatal infection. We previously demonstrated that 2 high doses of PMPA (at 30mg/kg subcutaneously, one dose given 4 hours before virus inoculation, and the 2nd dose 24 later) was effective in preventing infection. We now determine whether a lower dosage regimen of PMPA can still be effective, especially if PMPA is given only after virus inoculation. Results Twelve newborn macaques were inoculated with SIVmac251. Four untreated control infants became persistently infected. Of four animals given 2 doses of PMPA (4mg/kg) at - 4 and +20 h after virus inoculation, three animals remained uninfected and are healthy at 9 months of age. Of four animals given 2 doses of PMPA (4mg/kg) at +1 and +25 h after virus inoculation, two animals remained uninfected and are healthy at 9 months of age; the other animals became persistently infected. The animals which became persistently infected were used to test the efficacy of other antiviral drugs (3TC, FTC, D4FC) against established infection. Future directions Several human trials are currently being developed to test the potential of this PMPA regimen in developing countries. KEY WORDS PMPA, vertical transmission, primate, prophylaxis, prevention, pediatrics FUNDING NIH Grant RR00169